Efficacy and safety of atezolizumab/bevacizumab in patients with HCC after prior systemic therapy: A global, observational study

Background: Since the introduction of the combination treatment of anti-programmed death-ligand 1 antibody atezolizumab and anti-VEGF antibody bevacizumab (AB), median overall survival in HCC has drastically improved. However, evidence on the efficacy and safety of the novel treatment standard in patients with prior exposure to systemic treatment is scarce. The aim of this global, multicenter, observational study was to evaluate the efficacy and safety of AB in patients after previous systemic therapy. Methods: We screened our global, multicenter, prospectively maintained registry database for patients who received any systemic therapy before AB. The primary end point was overall survival; secondary end points were time-to-progression, progression-free survival, objective response rate, and safety (rate and severity of adverse events). Results: Among 493 patients who received AB for unresectable HCC, 61 patients received prior systemic therapy and were included in this analysis. The median age of the study population was 66 years, with 91.8% males. Predominant risk factors for HCC were viral hepatitis (59%) and alcohol (23%). Overall survival for AB was 16.2 (95% CI, 14.5–17.9) months, time-to-progression and progression-free survival were 4.1 (95% CI, 1.5–6.6) and 3.1 (95% CI, 1.1–5.1) months, respectively. The objective response rate was 38.2% (7.3% with complete and 30.9% with partial response). Overall survival was not influenced by treatment line (2nd vs. >2nd) or previous systemic treatment modality (tyrosine kinase inhibitors vs. immune checkpoint inhibitors). Treatment-related adverse events of all grades according to Common Terminology Criteria for Adverse Events were documented in 42.6% of patients, with only 13.1% of grade ≥3, including one death. Conclusion: In this observational study, AB emerges as a safe and efficacious treatment option in patients with HCC previously treated with other systemic therapy.


INTRODUCTION
Despite promising achievements in the treatment landscape of liver cancer, [1] incidence and mortality are drastically increasing.Predictions estimate 1.4 million new cases and 1.3 million deaths in 2040, which represents an increase in mortality by 56% compared with 2020. [2]e combination of anti-programmed death-ligand 1 antibody atezolizumab and anti-VEGF antibody bevacizumab has revolutionized systemic therapy for unresectable HCC, which represents the majority of primary liver cancer.Based on the IMbrave150 phase 3 clinical trial, this regimen has become the novel standard of care for first-line systemic therapy, [3,4] Abbreviations: AB, antibody bevacizumab; AE, adverse event; ALBI, albumin-bilirubin; BCLC, Barcelona Clinic Liver Cancer; CR, complete response; EBRT, external beam radiotherapy; ECOG PS, Eastern Cooperative Oncology Group performance status; ICI, immune checkpoint inhibitors; IO, immune-oncological therapy; NE, not estimable; OS, overall survival; TARE/TACE, transarterial radio/chemoembolisation; TKI, tyrosine kinase inhibitor; TTP, time-to-progression.
Vincent Joerg and Bernhard Scheiner contributed equally as first authors.
Kornelius Schulze and Johann von Felden contributed equally as senior authors.
[7][8] Experience of immunotherapy in the second line mostly includes nonrandomized, noncontrolled, or early-phase clinical studies [9][10][11][12][13] There are only 2 phase 3 clinical trials evaluating monotherapy with pembrolizumab against programmed cell death protein 1.However, they reported conflicting results.Early evidence from the KEYNOTE-394 study limited to an Asian population reported a survival benefit for pembrolizumab against placebo, while the global KEYNOTE-240 study failed to demonstrate the superiority of pembrolizumab against placebo. [14,15]he aim of this global, multicenter, real-world observational study was to assess the efficacy and safety of the combination therapy with atezolizumab and bevacizumab in patients with HCC who previously received other systemic therapies.

Patient enrollment
We generated a prospectively maintained database, termed atezolizumab bevacizumab (AB real), [16] including 493 patients who received atezolizumab and bevacizumab for unresectable HCC in 14 tertiary care centers across Europe, the United States, and Asia.The main inclusion criteria were (i) age ≥18 years, (ii) HCC diagnosis according to clinical guidelines, [17] and (iii) systemic therapy with atezolizumab and bevacizumab.Baseline characteristics and outcomes were provided from a medical chart review by each institution.For this project, patients who were treated with atezolizumab and bevacizumab as firstline systemic therapy were excluded (n = 432), and only patients who previously received any type of systemic therapy were kept as the study population (n = 61).
Clinical baseline characteristics, such as demographic data, etiology, and stage of underlying chronic liver disease or cirrhosis [Child-Turcotte-Pugh score, albuminbilirubin (ALBI) grade], were obtained by medical chart review and provided by each institution.Performance status as indicated by Eastern Cooperative Oncology Group, tumor stage according to the Barcelona Clinic Liver Cancer (BCLC) staging system, and laboratory tests were recorded at the start of therapy.Information about adverse events (AE) was assessed by local investigators and graded according to the Common Terminology Criteria for Adverse Events.
Among our study cohort, 13% (8/61) of patients were previously included in a retrospective analysis of atezolizumab and bevacizumab in HCC with progression after firstline therapy. [12]This applies to 3 patients contributed from Hamburg and 5 patients from Vienna.Data on the efficacy of atezolizumab and bevacizumab from the remaining 87% (53/61) patients have not been published yet.

Data analysis
The primary end point of the study was OS from the start of treatment with atezolizumab and bevacizumab.Secondary end points were time-to-progression (TTP),

Clinical characteristics
The overall prospective AB real database currently contains 493 patients from 14 centers globally.For this project, all patients who received previous systemic treatment before atezolizumab and bevacizumab were included in the analysis (n = 61) (Figure 1).Baseline characteristics are displayed in Table 1.The median age of the population was 66 (59-71) years, 91.8% of patients were male.Risk factors for HCC were distributed as follows: alcohol in 23%, viral hepatitis in 59%, NASH in 6.6%, and other risk factors in 19.7% of the population.In all, 72.1% of patients had liver cirrhosis.Liver function, according to Child-Pugh Score, was stage A5 in 42.6% (n = 26), A6 in 32.8% (n = 20), B7 in 14.8% (n = 9), B8 in 6.6% (4), B9 in 1.6% (1), and C11 in 1.6% (n = 1) of patients.Classification following the ALBI score resulted in 23 patients being classified as grade 1, 34 patients as grade 2, and 4 patients as grade 3. Performance status was mostly adequate, with 98.3% (n = 60) of patients being classified as Eastern Cooperative Oncology Group 0 or 1. Tumor stage was assessed according to BCLC staging criteria with 70.5% (n = 43) of In 4 (7%) patients, the reason for not starting atezolizumab and bevacizumab upfront was not well documented.Data on upper endoscopy before treatment initiation were available in 48 (79%) patients.Of these, n = 20 (42%) patients had varices at the treatment initiation.While most of these patients (n = 19) had esophageal varices, only 4 patients were diagnosed with gastric varices.Overall, 12 patients (60%) had small varices, 7 (35%) patients had medium-sized varices, and one (5%) patient was diagnosed with large varices.
There was no significant difference in median OS between patients receiving atezolizumab and F I G U R E 2 Median overall survival (A), progression-free survival (B), and time-to-progression (C) of the cohort.The latter analysis is limited to patients who had radiologic follow-up data available.
The proportion of patients experiencing AEs of any grade was not associated with the type of treatment modality (TKI or ICI) or ALBI grade.However, AEs were more common in patients treated in the second line as compared with later lines of treatment (second line: n = 20 (52.6%) vs. later lines: n = 6 (26.1%), p = 0.042) and numerically higher in patients with CPS class B (64.3%, n = 9/14) and C (100%, n = 1/1) as compared with patients with CPS A (34.8%, n = 16/46; p = 0.075).

DISCUSSION
To our knowledge, we report the first global, prospective, multicenter, observational cohort study on the combination of atezolizumab and bevacizumab for unresectable HCC in patients who were previously treated with at least 1 different systemic therapy regimen.Our data suggest strong efficacy of the combination therapy with a median OS of 16.2 months, objective response rates of 65.5%, and PFS and TTP of 4.1 and 3.1 months, respectively.As expected, the ALBI score was an independent predictor of impaired survival in Cox modeling, and patients stratified as grade 1 according to the ALBI score showed a median OS of 17.3 months.This is comparable to the outcome of patients treated with atezolizumab and bevacizumab in the first systemic line within the IMbrave150 trial [3,4] as well as in real-world studies. [16,19]As expected, compromised liver function resulted in a decreased median OS (11.6 mo for ALBI grade 2, 1.3 mo for ALBI grade 3), which is also in line with studies from first-line treatment. [20]mportantly, atezolizumab and bevacizumab treatment was not only effective but also safe, with an AE rate of 42.6% overall and an AE grade ≥ 3 rate of 13.1%.This rate is in line with the IMbrave150 trial [3,4] and other real-world studies [19] on first-line treatment with atezolizumab and bevacizumab.In particular, no grade 3 or higher immune-related events occurred, and only 6.6% of patients required corticosteroid treatment, which could be explained by the high number of patients previously tolerating ICI-based therapies.In conclusion, neither the further line setting nor the fact that we included 25% of patients with advanced liver disease (Child-Turcotte-Pugh B/C) seemed to compromise its safety.Comparable safety data have also been reported in other studies evaluating atezolizumab and bevacizumab in patients with advanced liver disease and impaired liver function. [19,21]t is highly likely that patients progressing to multiple lines of treatment while maintaining preserved liver function and adequate performance status will represent a selected HCC subgroup characterized by a favorable tumor biology.However, this is a potential bias inherent to any studies evaluating second-line treatment regimens, and until now, only limited data were available regarding the efficacy of the combination therapy with atezolizumab and bevacizumab in a further-line setting.][7] However, the median OS in these studies was only around 10 months (10.6 mo (95% CI, 9.1-12.1),10.2 months (95% CI, 9.1-12.0),and 8.5 months (95% CI, 7.0-10.6)for regorafenib, cabozantinib, and ramucirumab, [5][6][7] respectively).Noteworthy, objective tumor response rates were remarkably higher for the combination therapy compared to other agents, including our study with 38.2%, which is important as a recent meta-analysis including 34 randomized controlled trials in HCC concluded that achieving an objective response is associated with a significantly favorable prognosis. [22]he radiological responses observed in our study included 7.3% of patients with a CR, and in 1 patient, treatment with atezolizumab and bevacizumab could even be stopped due to an ongoing CR, a pattern of response that has hardly ever been observed in patients treated with TKI.
Systemic treatment sequencing remains challenging in patients with HCC. [23]Some earlier phase clinical trials have shown promising results for pembrolizumab or nivolumab monotherapy, and nivolumab in combination with ipilimumab in a second-line setting. [11,24,25]owever, while an Asian phase 3 clinical trial evaluating pembrolizumab against placebo in a second-line setting after sorafenib was positive, [14] the global phase 3 clinical trial did not meet its primary end point. [15]o our knowledge, there are only 2 studies specifically reporting real-world experience with atezolizumab and bevacizumab after previous systemic therapy, each with a smaller sample size and mostly national cohorts compared to our study.Most recently, a retrospective multicenter study included 12 German and 1 Austrian center and analyzed 50 patients who received atezolizumab and bevacizumab after at least 1 previous line of systemic therapy. [12]The authors reported a median OS of 16.0 months (95% CI 5.6-26.4),an objective response rate of 32%, and a disease control rate of 68%, almost identical to our results.Only the median PFS was higher compared to our cohort (7.1 mo, 95% CI 4.4-9.8).Notably, data from our study were collected prospectively and included a global cohort of patients from Europe, the United States, and Asia, which further strengthens the generalizability and reproducibility of our results.Another study from Japan limited their analysis to patients who were treated with molecular targeted therapy before receiving atezolizumab and bevacizumab and focused on tumor growth patterns.This study included 31 patients, of whom 20 patients were previously treated with lenvatinib while the remaining 11 patients received other molecular therapies, including sorafenib, regorafenib, and ramucirumab.Patients with prior lenvatinib treatment showed initial tumor growth followed by shrinkage under atezolizumab and bevacizumab, ultimately resulting in higher objective response rates (21% vs. 9%).However, this did not reach statistical significance and median OS was similar between groups as well (11.6 vs. 11.4 mo). [13]espite our promising findings regarding the efficacy and safety of atezolizumab and bevacizumab in subsequent treatment lines, our study has several limitations.First, the sample size, although multicenter and global, is rather small, and especially subgroup analyses must be considered exploratory and need to be confirmed in larger studies.Due to the variety of different prior systemic therapies and the limited sample size, subgroup analysis of specific prior treatment regimens was not possible.Secondly, we only included patients who actually received the combination treatment, which could render a selection bias toward patients with favorable tumor biology and other known (eg, age, performance status, and liver function) and unknown prognostic factors.Among our study cohort, 13% (8/61) of patients were previously included in a retrospective analysis of atezolizumab and bevacizumab in HCC with progression after first-line therapy. [12]n conclusion, our data suggest atezolizumab and bevacizumab as efficacious and safe alternative treatment regimens for patients after previous systemic therapy, including later treatment lines.Nevertheless, larger confirmatory studies are warranted, and the most efficacious sequence of systemic therapy after initial progression is yet to be determined in prospective studies.

F
I G U R E 3 Median overall survival stratified by ALBI grade.Abbreviation: ALBI, albumin-bilirubin.
the study with numbers of patients by each contributing center.Abbreviation: AB, antibody bevacizumab.
Includes 2 patients with cryptogenic liver disease, 1 patient with Wilson's disease, 1 patient with alpha-1-antitrypsin-associated liver disease, 1 patient with a history of liver adenoma that progressed to HCC and 6 patients with unknown etiology of liver disease/no underlying liver disease.
a b Patients can have multiple risk factors, i.e. numbers exceed 100%.cPatientscan have multiple previous treatments.n = 46) of patients received at least 1 treatment regimen containing a TKI.The best radiological response to the previous line of systemic treatment was evaluable in 48 (79%) patients.Of these, 1 (2%) patient had a complete response (CR), 6 (10%) had a partial response, 19 (31%) had stable disease, and 22 (36%) had progressive disease as their best radiological response.The most common reason for not starting atezolizumab and bevacizumab as a first-line systemic treatment was lack of approval at the time of systemic treatment initiation (n = 36, 59%), while another 31% of patients (n = 19) decided to participate in clinical trials testing other agents for first line.In 2 patients (3%), atezolizumab and bevacizumab were initially not started at first line due to safety concerns (1 patient with a history of dermatomyositis and fear of autoimmune reactivation, another one with concomitant radiotherapy).
T A B L E 2 Cox regression model for death Abbreviations: ALBI, albumin-bilirubin; BCLC, Barcelona Clinic for Liver Cancer classification; IO, immune-oncological therapy.ATEZO/BEV AFTER PRIOR SYSTEMIC THERAPY FOR HCC | 7